WO2004081010A1 - Composes ayant une activite au niveau du recepteur 5ht2c et leurs utilisations - Google Patents

Composes ayant une activite au niveau du recepteur 5ht2c et leurs utilisations Download PDF

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Publication number
WO2004081010A1
WO2004081010A1 PCT/EP2004/001844 EP2004001844W WO2004081010A1 WO 2004081010 A1 WO2004081010 A1 WO 2004081010A1 EP 2004001844 W EP2004001844 W EP 2004001844W WO 2004081010 A1 WO2004081010 A1 WO 2004081010A1
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WIPO (PCT)
Prior art keywords
methyl
compound
methoxy
phenyl
piperidin
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PCT/EP2004/001844
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English (en)
Inventor
Dieter Hamprecht
Fabrizio Micheli
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Glaxo Group Limited
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Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to US10/547,988 priority Critical patent/US20060281786A1/en
Priority to DE602004004378T priority patent/DE602004004378T2/de
Priority to JP2006504466A priority patent/JP2006519798A/ja
Priority to EP04713892A priority patent/EP1603914B1/fr
Publication of WO2004081010A1 publication Critical patent/WO2004081010A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment and/or prevention of CNS disorders and other disorders.
  • WO 96/23783, WO 97/46699 and WO 97/48700 all disclose a series of indoline derivatives which are 5-HT2C receptor antagonists and which are claimed to be useful in the treatment of various CNS disorders.
  • the present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Q is phenyl or a 6-membered heteroaromatic group containing at least one nitrogen atom
  • B is O, S or NR- 11 , wherein Rn is hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or is C ⁇ _ ⁇ alkanoyl optionally substituted by C -6 alkoxy;
  • R-] is halogen, cyano, Chalky!, C3_ycycloalkyl, Cs. cycloalkyloxy, C ⁇
  • R5 and Rg are independently hydrogen or C- j .galkyl); p is 0, 1 or 2 or 3;
  • R 2 is hydrogen, halogen, hydroxy, cyano, nitro, C-]_galkyl, C- ⁇ galkanoyl, C3_7cycloalkyl,
  • X is oxygen, sulfur, -CH 2 - or NR ⁇ wherein RQ is hydrogen or C-
  • _galkyl; Y is a single bond, -CH 2 -, -(CH 2 ) 2 - or -CH CH-; and Z is an optionally substituted N-linked heterocyclic group or a C-linked 4 to 7 membered heterocyclic group containing at least one nitrogen, or Z is -NRgR-io where Rg and R-J Q are independently hydrogen or C-
  • 6-membered heteroaromatic group containing at least one nitrogen atom refers to groups such as pyridyl, pyridazinyl, pyrinidinyl, pyrazinyl and triazinyl.
  • halogen and its abbreviated form “halo” are used herein to describe fluorine, chlorine, bromine or iodine.
  • alkyl is used herein to describe a straight chain or branched fully saturated hydrocarbon group.
  • .galkyl refers to alkyl groups having from one to six carbon atoms, including all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.
  • C ⁇ _galkanoyl refers to an alkanoyl group having from 1 to 6 carbon atoms, such as methanoyl (or “formyl”), ethanoyl (or “acetyl”), propanoyl, isopropanoyl, butanoyl, isobutanoyl, sec-butanoyl, pentanoyl, neopentanoyl, sec-pentanoyl, isopentanoyl, tertpentanoyl and hexanoyl.
  • methanoyl or “formyl”
  • ethanoyl or “acetyl”
  • propanoyl isopropanoyl
  • butanoyl isobutanoyl
  • sec-butanoyl sec-butanoyl
  • pentanoyl neopentanoyl
  • sec-pentanoyl sec-pentanoyl
  • C ⁇ _galkoxy refers to a straight chain or branched chain alkoxy (or “alkyloxy”) group having from one to six carbon atoms, including all isomeric forms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy, sec-pentoxy, n-pentoxy, isopentoxy, tert-pentoxy and hexoxy.
  • Cs./cycloalkyl refers to a cycloalkyl group consisting of from 3 to 7 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.
  • Optional substituents for C3_7cycloalkyl includes one or more halogen, hydroxy, oxo, C-
  • C-]_galkylthio refers to a straight chain or branched chain alkylthio group having from one to six carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio, sec-pentylthio, n-pentylthio, isopentylthio, tert-pentylthio and hexylthio.
  • mono- or di-Ci-galkylamino refers to an amino group which is substituted by one C-
  • monoC1-6alkylamino include methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, sec- butylamine, tert-butylamine, pentylamine, neopentylamine, sec-pentylamine, n- pentylamine, isopentylamine, tert-pentylamine and hexylamine.
  • di-C1- 6alkylamino examples include dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, disec-butylamine, ditert-butylamine, dipentylamine, dineopentylamine, dihexylamine, butylmethylamino, isopropylmethylamino, ethylisopropylamino, ethylmethylamino, etc.
  • aryl is used herein to describe 5 to 7-membered monocyclic or 9 to 11- membered bicyclic aromatic carbocyclic groups such as phenyl or naphthyl, or monocyclic or bicyclic heteroaromatic groups such as pyrrolyl, furyl, thienyl, pyrrolinyl, imidazolyl, pyrazolyl, pyrazolinyl, thiazolyl, isoxazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, benzimidazolyl, benzoxazolyl, benzothienyl, quinolyl, quinoxalinyl, quinazolinyl and isoquinolyl; all of which may be optionally substituted by one or more of C
  • .galkoxy or "haloC ⁇ _galkyl” are used to describe a C-
  • heterocyclic group is used herein to describe an aromatic or non-aromatic ring containing 1 , 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen.
  • 4 to 7 membered heterocyclic groups include azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolinyl, isothiazolidinyl, thiazolidinyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azepinyl, azepanyl, dioxolanyl, thienyl, tetrahydrothienyl,
  • N-linked heterocyclic group is used herein to describe a heterocyclic group which is linked to the remainder of the molecule via a nitrogen atom.
  • Suitable examples of 4 to 7 membered N-linked heterocyclic groups include azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolinyl, isothiazolidinyl, thiazolidinyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, piperidyl, piperazinyl, morpholinyl and azepanyl.
  • C-linked heterocyclic group containing at least one nitrogen is used herein to describe a heterocyclic group which is contains at least one nitrogen atom and is linked to the remainder of the molecule via a carbon atom.
  • Suitable examples of 4 to 7 membered C-linked heterocyclic groups containing at least one nitrogen include azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, piperidyl, piperazinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azepinyl and azepanyl. More than one optional substituent may be present in the N-linked or C-linked heterocycle, which may be the same or different, and may be attached to any carbon atom of the heterocycle or an available nitrogen atom.
  • Suitable optional substituents for the N-linked or C-linked heterocycle include C ⁇ _galkyl, amino, mono- or di- C-j.galkylamino, aryl, arylC ⁇
  • aromatic or non-aromatic heterocycleC ⁇ _ galkyl examples include heterocycle-methyl (such as pyridinyl-methyl and benzimidazolyl-methyl) and heterocycle-ethyl (such as morpholinyl-ethyl and indolyl-ethyl).
  • Substituents in the N-linked or C-linked heterocycle may form a bridge structure, to form a group such as for example 2-oxa-5-azabicyclo[2.2.1]heptyl.
  • Such a bicyclic group may be further substituted by the substituents listed above. More than one substituent may be present on the same carbon atom to form spiro structures such as 1 ,4 and 1 ,5 dioxa spiro compounds.
  • A is a group -(CHR3)-, preferably R3 is hydrogen.
  • A is -CH 2 -.
  • R-j may be the same or different.
  • R-] is/are halogen, particularly chloro or fluoro.
  • Preferab y R 2 is C-
  • Preferab y X is oxygen
  • Preferab y Y is -CH 2 -.
  • y Z is an optionally substituted N-linked 4 to 7 membered heterocycle, in particular piperidyl.
  • Preferred substituents include halogen (particularly fluoro) and C- j . galkyl (particularly methyl).
  • Preferred compounds are compounds of formula (la):
  • Preferred compounds include:
  • the compounds of formula (I) can form acid addition salts. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid
  • organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-to
  • the compounds of this invention may be in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. geometric or ⁇ "cis-trans") isomers, diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:
  • L is mesylate.
  • the reaction may take place in a solvent such as DMF in the presence of sodium iodide and potassium carbonate.
  • LG is a leaving group such as halogen, for example chloro or bromo, or a sulfonate ester, for example mesyl or tosyl.
  • Rx is alkyl, for example
  • reaction may take place in a solvent such as DMF at elevated temperature, suitably 100 °C. Where this reaction does not lead to spontaneous cyclisation of the intermediate alkylation product this material is treated with AIMe 3 or a similar oxophilic reagent.
  • Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques.
  • a compound wherein A is -(HCOH)- may be converted to a compound wherein A is -(CH 2 )- by using a suitable reducing agent such as triethylsilane-trifluoroacetic acid using dichloromethane as solvent;
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);, fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate);, tabletting lubricants lubricants (e.g. magnesium stearate, talc or silica);, disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • tabletting lubricants lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non- aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of the invention may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • the compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
  • the compounds of the present invention have affinity for the 5-HT 2 c receptor.
  • the affinity can be determined by assessing their ability to displace [ ⁇ j-mesulergine from rat or human 5-HT 2 clones expressed in 293 cells in vitro, as described in WO 94/04533.
  • Example compounds were tested according to this assay and were found to have pKi values >5.8. Some compounds show a considerably higher affinity in the range of 7.0 to >9.0 in human cells.
  • the intrinsic activity of the compounds of this invention can be determined according to the [ 35 S]GTP ⁇ S functional assay which is described in WO 99/07700.
  • Compounds of formula (I) and their pharmaceutically acceptable salts are of use in the treatment of certain CNS disorders such as depression (which term is used herein to include bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia for example of the Alzheimer's type, vascular dementia with depressed mood, schizoaffective disorder or the depressed type, and depressive disorders resulting from general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc), anxiety including generalised anxiety and social anxiety disorder, schizophrenia, panic disorder, agoraphobia, social phobia, epilepsy, obsessive compulsive disorder and post-traumatic stress disorder, pain (particularly neuropathic pain), migraine, memory disorders, including dementia, amnesic disorders
  • sedative ipnotic e.g. dextroamphetamine, methylamphetamine
  • amphetamine or amphetamine-related drugs e.g. dextroamphetamine, methylamphetamine
  • Alzheimer's disease motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders, disorders associated with spinal trauma and/or head injury such as hydrocephalus, gastrointestinal disorders such as IBS (Irritable Bowel Syndrome), Crohn's disease, ulcerative colitis, non-steroidal anti- inflammatory drug induced damage) as well as microvascular diseases such as macular oedema and retinopathy.
  • IBS Irritable Bowel Syndrome
  • Crohn's disease Crohn's disease
  • ulcerative colitis non-steroidal anti- inflammatory drug induced damage
  • microvascular diseases such as macular oedema and retin
  • treatment refers to alleviation of established symptoms as well as prophylaxis.
  • the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of the above disorders.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutic substance in the treatment of a CNS disorder.
  • the CNS disorder is depression and/or anxiety.
  • Compounds of the invention may be administered in combination with other active substances such as 5HT3 antagonists, NK-1 antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.
  • active substances such as 5HT3 antagonists, NK-1 antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.
  • 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • the invention further provides a method of treatment of the above disorders in mammals including humans, which comprises administering to the sufferer a therapeutically safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides a a method of treatment of a CNS disorder in mammals including humans, which comprises administering to the sufferer a therapeutically safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the disorder is depression and/or anxiety.
  • the invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a CNS disorder.
  • the CNS disorder is depression and/or anxiety.
  • composition of the present invention may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months. When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.
  • Typical scale 5 mmol To NaH (60% in mineral oil, 2.3 eq.) in dry DMF (20 ml per 1 g 60% NaH) at 0 °C was added portionwise over 20 min via syringe with vigorous stirring acetylacetate methyl ester (2.1 eq.). After 10 min this mixture was allowed to warm to 25 °C and added to a stirred reaction vessel cooled in an ice bath containing the substituted 2-nitro-fluorobenzene (1.0 eq.). After 45 min the mixture was allowed to warm to 25 °C. After 16 h excess aqueous HCI (2 M) was added followed by water and Et 2 O. The layers were mixed, to give the substituted 2-(2-nitro-phenyl)-3-hydroxy-but-2-enoic acid methyl ester compounds.
  • the product was obtained as a yellow oil (0.88 g) containing impurities as judged by NMR.
  • 6-Bromo-2-bromomethyl-5-methoxy-2-methyl-1 H-indole-3-carboxylic acid methyl ester (P6, 29 mg) and 4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenylamine hydrochloride (P2, 1.1 eq.) were heated in dry DMF (0.5 ml) for 2 h at 120 °C. NaHCO 3 (ca. 100 mg) was added and heating continued for additional 2 h. The mixture was concentrated in vacuo and the residue submitted to column chromatography.

Abstract

L'invention porte sur des composés de formule (I) et sur des sels de ceux-ci acceptables d'un point de vue pharmaceutique. Dans cette formule, Q représente phényle ou un groupe hétéroaromatique à 6 éléments contenant au moins un atome d'azote; A représente -(CH2-CH2)-, -(CH=CH)-, -(CH2)3-, -C(CH3)2-, -(CH=CH-CH2)-, ou un groupe -(CHR3)- où R3 représente hydrogène, halogène, hydroxy, cyano, nitro, C1-6alkyle, C3-7cycloalkyle, C3-7cycloalkyloxy, haloC1-6alkyle, C1-6alcoxy, haloC1-6alcoxy or C1-6alkylthio; B représente O, S ou NR11, R11 représentant hydrogène, C1-6alkyle éventuellement substitué par C1-6alcoxy, ou représente C1-6alcanoyle éventuellement substitué par C1-6alcoxy; R1 représente halogène, cyano, C1-6alkyle, C3-7cycloalkyle, C3-7cycloalkyloxy, C1-6alcoxy, C1-6alkylthio, hydroxy, amino, mono- ou di-C1- 6alkylamino, un groupe hétérocyclique à liaison N composé de 4 à 7 éléments, nitro, haloC1-6alkyle, haloC1-6alcoxy, aryle, arylC1-6alkyle, arylC1-6alkyloxy, arylC1-6alkylthio, COR4 (R4 représentant amino, mono- ou di-C1-6alkylamino ou un groupe hétérocyclique à liaison N composé de 4 à 7 éléments), COOR5 ou COR6 (R5 et R6 représentant indépendamment hydrogène ou C1-6alkyle); p est égal à 0, 1 ou 2 ou 3; R2 représente hydrogène, halogène, hydroxy, cyano, nitro, C1-6alkyle, C1-6alcanoyle, C3-7cycloalkyle, C3-7cycloalkyloxy, haloC1-6alkyl, C1-6alcoxy, haloC1-6alcoxy, C1-6alkylthio, amino, mono- ou di-C1-6alkylamino ou un groupe hétérocyclique à liaison N composé de 4 à 7 éléments; X représente oxygène, soufre, -CH2- ou NR8, R8 représentant hydrogène ou C1-6alkyle; Y représente une double liaison, -CH2-, -(CH2)2- ou -CH=CH-; et Z représente un groupe hétérocyclique à liaison N éventuellement substitué ou un groupe hétérocyclique à liaison C composé de 4 à 7 éléments contenant au moins un azote ou Z représente -NR9R10, R9 et R10 représentant, indépendamment, hydrogène ou C1-6alkyle. L'invention porte également sur un procédé de préparation de ces composés et sur leurs utilisations thérapeutiques, comme, par exemple, dans le traitement de la dépression et de l'anxiété.
PCT/EP2004/001844 2003-03-11 2004-02-24 Composes ayant une activite au niveau du recepteur 5ht2c et leurs utilisations WO2004081010A1 (fr)

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US10/547,988 US20060281786A1 (en) 2003-03-11 2004-02-24 Compounds having activity at 5ht2c receptor and uses thereof
DE602004004378T DE602004004378T2 (de) 2003-03-11 2004-02-24 Verbindungen mit einer 5-ht2c rezeptor-wirkung und ihre verwendung
JP2006504466A JP2006519798A (ja) 2003-03-11 2004-02-24 ５ＨＴ２ｃ受容体に活性を有する化合物及びその使用
EP04713892A EP1603914B1 (fr) 2003-03-11 2004-02-24 Composes ayant une activite au niveau du recepteur 5ht2c et leurs utilisations

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GBGB0305553.0A GB0305553D0 (en) 2003-03-11 2003-03-11 Compounds
GB0305553.0 2003-03-11

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JP (1) JP2006519798A (fr)
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ES (1) ES2276281T3 (fr)
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WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
US7994336B2 (en) 2006-08-15 2011-08-09 Actelion Pharmaceuticals Ltd. Azetidine compounds as orexin receptor antagonists
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale

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WO1997048700A1 (fr) * 1996-06-20 1997-12-24 Smithkline Beecham Plc Derives de l'indoline utiles comme antagonistes des recepteurs 5ht-2c
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WO1997048700A1 (fr) * 1996-06-20 1997-12-24 Smithkline Beecham Plc Derives de l'indoline utiles comme antagonistes des recepteurs 5ht-2c
WO2003089409A1 (fr) * 2002-04-19 2003-10-30 Glaxo Group Limited Composes presentant une affinite avec le recepteur 5ht2c et utilisation therapeutique de ceux-ci

Cited By (19)

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EP2400300A1 (fr) 2004-08-25 2011-12-28 Takeda Pharmaceutical Company Limited Procédé de sélection d'agents préventifs/remèdes pour l'incontinence de stress
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
EP2742936A1 (fr) 2006-05-16 2014-06-18 Takeda Pharmaceutical Company Limited Composé hétérocyclique condensé et son utilisation
EP2727585A1 (fr) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited Méthode de dépistage in-vivo
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
US7994336B2 (en) 2006-08-15 2011-08-09 Actelion Pharmaceuticals Ltd. Azetidine compounds as orexin receptor antagonists
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2789338A2 (fr) 2007-11-15 2014-10-15 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
US9650378B2 (en) 2008-01-11 2017-05-16 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9296743B2 (en) 2008-01-11 2016-03-29 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale

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US20060281786A1 (en) 2006-12-14
GB0305553D0 (en) 2003-04-16
JP2006519798A (ja) 2006-08-31
DE602004004378D1 (de) 2007-03-08
EP1603914B1 (fr) 2007-01-17
DE602004004378T2 (de) 2007-05-31
EP1603914A1 (fr) 2005-12-14
ES2276281T3 (es) 2007-06-16

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